Towards Light‐Activated Ruthenium–Arene (RAPTA‐Type) Prodrug Candidates

• Published in: Chembiochem : a European journal of chemical biology 2019-11, Vol.20 (22), p.2876-2882
• Main Authors: Renfrew, Anna K., Karges, Johannes, Scopelliti, Rosario, Bobbink, Felix D., Nowak‐Sliwinska, Patrycja, Gasser, Gilles, Dyson, Paul J.
• Format: Article
• Language: English
• Subjects: Antineoplastic drugs; Antitumor agents; Benzene; bioinorganic chemistry; cancer; Cervical cancer; Cervical carcinoma; Cervix; Chemical Sciences; Chemotherapy; Coordination chemistry; Coordination compounds; Cymene; Cytotoxicity; Drug development; Drug resistance; Drugs; Epithelium; Exposure; Ligands; Medicinal Chemistry; photoactivated chemotherapy (PACT); prodrugs; Retina; Retinal pigment epithelium; Ruthenium; Ruthenium compounds; Side effects; Toluene; Toxicity
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201900236

Cancer is currently one of the deadliest diseases worldwide. Based on the high incidence of this disease, the side effects associated with current chemotherapies and the appearance of drug resistance, considerable efforts have been directed towards the development of new anticancer drugs with new modes of action. Metal‐based compounds are particularly attractive candidates due to their metabolic mechanisms, which differ substantially from those of organic drugs. Of special interest in this context are organometallic ruthenium(II) complexes of the type [Ru(η6‐arene)(pta)Cl2] (arene: p‐cymene, toluene, benzene, etc.; pta: 1,3,5‐triaza‐7‐phosphaadamantane), which are abbreviated to RAPTA. Complementary to chemotherapy, photoactivated chemotherapy is a technique that has received increasing attention towards the development of treatment for numerous kinds of cancer. With this in mind, a photoactive RAPTA‐type complex bearing azide ligands has been designed. The diazide complex, [Ru(η6‐p‐cymene)pta‐(N3)2], is inert in water, but slowly releases the azide ligand upon exposure to light. Consequently, the in vitro cytotoxicity of the complex in the dark and upon light exposure at λ=450 nm in human cervical carcinoma (HeLa) and noncancerous retinal pigment epithelium (RPE‐1) cells was investigated. Although the cytotoxicity of the complex was found to be modest in the dark, an increase in toxicity upon light exposure was observed. Make a PACT: A diazide complex, [Ru(η6‐p‐cymene)pta(N3)2] (pta: 1,3,5‐triaza‐7‐phosphaadamantane), is inert in water, but slowly releases the azide ligand upon exposure to light. The in vitro cytotoxicity of the complex in the dark and upon light exposure in human cervical carcinoma and noncancerous retinal pigment epithelium cells is investigated.